US2014213538A1PendingUtilityA1
Lysophosphatidic acid receptor antagonists
Est. expiryJan 15, 2033(~6.5 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 29/00A61P 11/00C07D 495/04C07D 261/14C07D 401/12C07D 491/048C07D 413/12C07D 413/10C07D 487/04C07D 513/04A61P 19/00C07D 405/10C07D 417/10C07D 275/03A61K 9/007C07H 15/26
44
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Claims
Abstract
Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with one or more of the lysophosphatidic acid receptors are provided.
Claims
exact text as granted — not AI-modified1 .- 32 . (canceled)
33 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
A is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when A is a ring system, it is optionally substituted;
B is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when B is a ring system, it is optionally substituted;
C is a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 5-11 membered heterocyclyl, and 5-11 membered carbocyclyl, wherein C is optionally substituted;
D is selected from —OH,
—NR 13 SO p R 14 , —C(O)—NR 13 SO p R 14 ,
—SO p R 15 , —SO p NR 16 R 17 , or carboxylic acid isosteres;
E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
L 4 is selected from
or alternatively,
wherein
is selected from:
or optionally substituted variants thereof;
L 1 is selected from a single bond, a —CH 2 — linker,
a —C≡C— linker, a —CH═CH— linker, or a ═C(R 11 )— linker;
L 2 is selected from a single bond, a —CH 2 — linker,
a —C≡C— linker, or a —CH═CH— linker;
L 3 is absent or selected from
or a ═C(R 11 )— linker;
L 5 is selected from
or a —C≡C— linker;
W is selected from C(R 6 ) 2 , NR 6 , or O;
X is selected from —C(O) or S(O) p ;
each Y is independently selected from CR 6 or N;
Y 1 is selected from C(R 6 ) 2 , NR 6 , or O;
each Y 4 is independently absent, CR 9 , C(R 9 ) 2 , N, or NH, provided that only one Y 4 can be absent;
each Z is independently selected from C(O), O, S, S(O) 2 , NR 6a , C(O)NR 6b , or S(O) 2 NR 6c ;
R 1 is selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl; or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
R 2 and R 3 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each of cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 2 or R 3 is optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
or R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
or R 2 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl and R 3 is joined to an atom alpha to a point of attachment of L 5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent; or R 3 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R 2 is joined to an atom alpha to a point of attachment of L 5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
each R 4 and R 5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; or R 4 and R 5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
each R 6 , R 6a , R 6b , and R 6c is independently selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; aryl; or C 3-6 cycloalkyl;
each R 7 and R 8 is independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; or R 7 and R 8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
each R 9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen; or two adjacent R 9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
each R 10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; aryl; C 3-6 cycloalkyl; or cyano;
each R 11 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; haloalkyl; or cyano;
each R 13 and R 14 is independently selected from hydrogen, alkyl, haloalkyl, aryl, or C 3-6 cycloalkyl;
R 15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C 3-6 cycloalkyl;
each R 16 and R 17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C 3-6 cycloalkyl; or R 16 and R 17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
each R 2a , R 3a , R 2b , R 3b , R 2c , and R 3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or each of R 2a and R 3a , R 2b and R 3ab , or R 2c and R 3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
m is independently an integer from 0-3;
n is an integer from 0-3;
k is an integer from 0-3;
p is an integer from 1-2;
q is an integer from 1-6;
each s and u is independently an integer from 0 to 6; and
represents a single or double bond, provided that
when A is
B is
D is —C(O)OH; m is 0; E is absent;
L 5 is —CH 2 SCH 2 CH 2 —; L 1 is a single bond; L 2 is a single bond; and
wherein R 9 is selected from H or halogen and R 4 is methyl; then C is not
34 . (canceled)
35 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein
A is an acetylene or selected from the group consisting of
wherein each * is a point of attachment of A to L 1 or L 3 , and wherein the rings in A are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo;
B is an acetylene or selected from the group consisting of
wherein each * is a point of attachment of B to L 1 or L 3 , wherein the rings in B are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo;
G together with the atoms to which it is attached forms a ring system selected from 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein the ring system is unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, or oxo;
is selected from
or optionally substituted variants thereof;
each Y 2 is independently selected from —CH═ or N;
each Y 3 is independently selected from C(R 6 ) 2 , NR 6 , O or S;
each Y 5 is independently selected from NR 6 , O or S; and
each R 12 is independently selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; acyl; C-carboxy; C-amido; sulfinyl; sulfonyl; or S-sulfonamido.
36 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein the compound of Formula (II) is also represented by Formula (IIa)
wherein
A is selected from acetylene,
wherein the rings in A are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
B is selected from acetylene,
wherein the rings in B are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
L 1 is selected from a single bond, a —C(O)— linker, a —CH 2 — linker, or a —CH 2 O-linker;
L 2 is selected from a single bond, a —O— linker, a —NH— linker, a —C(O)— linker, a CH 2 — linker, or a —CH 2 O— linker; and
R 4 is selected from hydrogen or alkyl optionally substituted with halogen.
37 . (canceled)
38 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein the compound of Formula (II) is also represented by Formula (IIb):
wherein L 5 is
39 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is absent.
40 . (canceled)
41 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is selected from
each optionally substituted with one or more halogens.
42 . (canceled)
43 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is selected from
44 . (canceled)
45 . (canceled)
46 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is selected from
each optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
47 . (canceled)
48 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is selected from
each optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
49 . (canceled)
50 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein E is selected from
each optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
51 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein D is —C(O)OR 1 .
52 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein the compound of Formula (II) is also represented by Formula (IIc):
53 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein A is
and B is selected from acetylene,
and wherein each of the rings in A or B is unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
54 . (canceled)
55 . The compound or pharmaceutically acceptable salt thereof of claim 53 , wherein B is an acetylene.
56 . The compound or pharmaceutically acceptable salt thereof of claim 53 , wherein B is
optionally substituted with one or more halogens.
57 . (canceled)
58 . (canceled)
59 . The compound or pharmaceutically acceptable salt thereof of claim 53 , wherein A is
optionally substituted with one or more halogens.
60 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein B is
and A is selected from acetylene,
wherein each of the rings in A or B is unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
61 . (canceled)
62 . The compound or pharmaceutically acceptable salt thereof of claim 60 , wherein A is an acetylene.
63 . The compound or pharmaceutically acceptable salt thereof of claim 60 , wherein A is
optionally substituted with one or more halogens.
64 . (canceled)
65 . (canceled)
66 . (canceled)
67 . (canceled)
68 . (canceled)
69 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein C is selected from
70 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein C is selected from
71 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein C is selected from
wherein R 10 is selected from hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl.
72 . The compound or pharmaceutically acceptable salt thereof of claim 71 , wherein C is selected from
73 . (canceled)
74 . (canceled)
75 . (canceled)
76 . (canceled)
77 . (canceled)
78 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein m is 0.
79 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein m is 1.
80 . (canceled)
81 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein each of R 2 and R 3 is hydrogen.
82 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein at least one of R 2 and R 3 is alkyl, aryl or halogen.
83 . The compound or pharmaceutically acceptable salt thereof of claim 82 , wherein both R 2 and R 3 are alkyl.
84 . The compound or pharmaceutically acceptable salt thereof of claim 82 , wherein one of R 2 or R 3 is alkyl and the other R 2 or R 3 is halogen.
85 . The compound or pharmaceutically acceptable salt thereof of claim 82 , wherein both R 2 and R 3 are halogens.
86 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted azetidine, an optionally substituted oxetane, an optionally substituted beta-lactam, an optionally substituted tetrahydropyran, an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl.
87 . The compound or pharmaceutically acceptable salt thereof of claim 86 , wherein R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted cyclopropyl, cyclobutyl or cyclopentyl.
88 . (canceled)
89 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein R 6 is hydrogen.
90 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein each of L 1 and L 2 is a single bond.
91 . (canceled)
92 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein L 5 is
93 . (canceled)
94 . The compound or pharmaceutically acceptable salt thereof of claim 92 , wherein both s and u in L 5 are an integer of 0.
95 . The compound or pharmaceutically acceptable salt thereof of claim 94 , wherein L 5 is —NH—.
96 . The compound or pharmaceutically acceptable salt thereof claim 94 , wherein L 5 is —C(O)—NH—.
97 . The compound or pharmaceutically acceptable salt thereof of claim 94 , wherein L 5 is —O—.
98 . (canceled)
99 . (canceled)
100 . (canceled)
101 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein R 1 is hydrogen or alkyl.
102 . (canceled)
103 . The compound or pharmaceutically acceptable salt thereof of claim 33 , wherein
104 . (canceled)
105 . (canceled)
106 . (canceled)
107 . The compound or pharmaceutically acceptable salt thereof of claim 33 , selected from compounds of Tables 2, 2A, 2B, 2C and 2D, and pharmaceutically acceptable salts thereof.
108 . The compound or pharmaceutically acceptable salt thereof of claim 33 , selected from compounds IT005, IT006, IT155, IT194-IT199, IT226-IT232, IT238, IT256-259, IT277, IT300, IT301, IT303-IT316, IT344, IT345, IT355, IT356, IT368, IT374, IT375, IT388, IT398-IT409, IT417, IT419, IT420, IT423-IT425, IT428-IT432, IT434-IT440, IT444, IT446-IT457, IT459-IT474, IT476-IT478, IT481-IT492, IT495, IT497, or IT500-IT514 of Table 13.
109 .- 440 . (canceled)
441 . A compound of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of
wherein A is optionally substituted;
is selected from
or optionally substituted variants thereof; wherein each * is a point of attachment of C to L 2 ;
D is selected from —OH,
—NR 13 SO p R 14 , —C(O)—NR 13 SO p R 14 ,
—SO p R 15 , —SO p NR 16 R 17 , or carboxylic acid isosteres;
E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
L 4 is selected from
or alternatively,
wherein
is selected from:
or optionally substituted variants thereof;
L 2 is selected from a single bond, a —CH 2 — linker,
a —C≡C— linker, or a —CH═CH— linker;
L 5 is selected from a single bond, a —CH═CH— linker, a —C≡C— linker,
or a 4-7 membered heterocyclyl;
W is selected from C(R 6 ) 2 , NR 6 , or O;
X is selected from —C(O) or S(O) p ;
each Y is independently selected from CR or N;
Y 1 is selected from C(R 6 ) 2 , NR 6 , or O;
each Y 2 is independently selected from —CH═ or N;
each Y 3 is independently selected from C(R 6 ) 2 , NR 6 , O or S;
each Y 4 is independently absent, CR 9 , C(R 9 ) 2 , N, or NH, provided that only one Y 4 can be absent;
each Z is independently selected from C(O), O, S, S(O) 2 , NR 6a , C(O)NR 6b , or S(O) 2 NR 6c ;
R 1 is selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl, or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
R 2 and R 3 are each independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each of cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 2 or R 3 is optionally substituted with one or more substituents selected from alkyl, amino, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or oxo;
or R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
or R 2 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl and R 3 is joined to an atom alpha to a point of attachment of L 5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent; or R 3 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R 2 is joined to an atom alpha to a point of attachment of L 5 to A to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl when E is absent;
each R 4 and R 5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; or R 4 and R 5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
each R 6 , R 6a , R 6b , and R 6c is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, halogen, aryl, or C 3-6 cycloalkyl;
each R 7 and R 8 is independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or R 7 and R 8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
each R 9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen, or two adjacent R 9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
each R 10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, halogen, aryl, C 3-6 cycloalkyl, or cyano;
each R 12 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, acyl, C-carboxy, C-amido, sulfinyl, sulfonyl, or S-sulfonamido.
each R 13 and R 14 is independently selected from hydrogen, alkyl, haloalkyl, halogen, aryl, or C 3-6 cycloalkyl;
R 15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C 3-6 cycloalkyl;
each R 16 and R 17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C 3-6 cycloalkyl; or R 16 and R 17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
each R 2a , R 3a , R 2b , R 3b , R 2c , and R 3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or each of R 2a and R 3a , R 2b and R 3b , or R 2c and R 3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
m is independently an integer from 0-3;
n is an integer from 0-3;
p is an integer from 1-2;
q is an integer from 1-6;
each s and u is independently an integer from 0 to 6; and
represents a single or double bond.
442 . (canceled)
443 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein
C is selected from the group consisting of
wherein C is unsubstituted or substituted with one or more substituents selected from C 1-3 alkyl optionally substituted with halogen or C 1-3 alkoxy, C 1-6 alkoxy, C 3-6 cycloalkyl, halogen, or cyano.
444 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein the compound of Formula (XI) is also represented by Formula (XIa):
wherein A is selected from the group consisting of
wherein the rings in A are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
445 . (canceled)
446 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein A is selected from
each unsubstituted or substituted with one or more substituents selected from alkyl, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
447 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein A is optionally substituted
448 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein D is —C(O)OR 1 .
449 . The compound or pharmaceutically acceptable salt thereof of claim 448 , wherein R 1 is hydrogen or unsubstituted alkyl.
450 . The compound or pharmaceutically acceptable salt thereof of claim 448 , wherein R 1 is alkyl substituted with one or more substituents selected from the group consisting of alkoxy, C-amido, O-carboxy, and 6 membered heterocyclyl, or optionally substituted aryl.
451 . (canceled)
452 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein m is 0.
453 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein m is 1.
454 . (canceled)
455 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein each of R 2 and R 3 is hydrogen.
456 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein one of R 2 or R 3 is hydrogen and the other R 2 or R 3 is alkyl or aryl.
457 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted azetidine, an optionally substituted oxetane, an optionally substituted beta-lactam, an optionally substituted tetrahydropyran, an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, or an optionally substituted cyclohexyl.
458 . The compound or pharmaceutically acceptable salt thereof of claim 457 , wherein R 2 and R 3 are joined together with the atom to which they are attached to form an optionally substituted cyclopropyl.
459 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein R 6 is hydrogen.
460 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein R 6 is C 1-3 alkyl.
461 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein each of L 5 and L 2 is a single bond.
462 . (canceled)
463 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein R 4 is alkyl or haloalkyl.
464 . (canceled)
465 . The compound or pharmaceutically acceptable salt thereof of claim 441 , wherein
466 . (canceled)
467 . (canceled)
468 . (canceled)
469 . The compound or pharmaceutically acceptable salt thereof of claim 441 , selected from compounds of Table 10A.
470 . The compound or pharmaceutically acceptable salt thereof of claim 441 , selected from compounds IT017, IT070, IT082-IT090, IT095, IT097, IT098, IT100, IT101, IT103, IT104, IT106, IT107 IT108, IT109, IT110, IT114 IT115, and IT116, IT118, and IT127 of Table 13.
471 . A compound of Formula (XII):
or a pharmaceutically acceptable salt thereof, wherein:
A is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when A is a ring system, it is optionally substituted;
B is an acetylene or a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein when B is a ring system, it is optionally substituted;
C is a ring system selected from the group consisting of 6-11 membered aryl, 5-11 membered heteroaryl, 5-11 membered heterocyclyl, and 5-11 membered carbocyclyl, wherein C is optionally substituted;
D is selected from —OH,
—NR 13 SO p R 14 , —C(O)—NR 13 SO p R 14 ,
—SO p R 15 , —SO p NR 16 R 17 , or carboxylic acid isosteres;
E is absent or selected from 6-10 membered arylene, 3-11 membered carbocyclyl, 3-11 membered heterocyclyl or 5 to 10 membered heteroarylene, wherein E is optionally substituted;
L 4 is selected from
or alternatively,
wherein
is selected from:
or optionally substituted variants thereof;
L 1 is selected from a single bond, a —CH 2 — linker,
a —C≡C— linker, a —CH═CH— linker, or a ═C(R 11 )— linker;
L 2 is selected from a single bond, a —CH 2 — linker,
a —C≡C— linker, or a —CH═CH— linker;
L 3 is absent or selected from
or a ═C(R 11 )— linker;
L 5 is selected from a single bond, a —CH═CH— linker, a —C≡C— linker,
or a 4-7 membered heterocyclyl;
W is selected from C(R 6 ) 2 , NR 6 , or O;
X is selected from —C(O) or S(O) p ;
each Y is independently selected from CR 6 or N;
Y 1 is C(R 6 ) 2 , NR 6 , or O;
each Y 4 is independently absent, CR 9 , C(R 9 ) 2 , N, or NH, provided that only one Y 4 can be absent;
each Z is independently selected from C(O), O, S, S(O) 2 , NR 6a , C(O)NR 6b , or S(O) 2 NR 6c ;
R 1 is selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, C-amido, O-carboxy, and 5-7 membered heterocyclyl; or aryl optionally substituted with one or more substituents selected from group consisting of amino, cyano, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, C-amido, N-amino, C-carboxy, O-carboxy and nitro;
R 2 and R 3 are each independently selected from hydrogen, halogen, haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-10 membered heteroaryl; wherein each C 3-7 cycloalkyl, 3-7 membered heterocyclyl, and 5-10 membered heteroaryl of R 2 or R 3 is optionally substituted; provided that R 2 and R 3 cannot both be hydrogen;
or R 2 and R 3 are joined together with the atom to which they are attached to form a halo-substituted C 3-7 cycloalkyl or halo-substituted 3-7 membered heterocyclyl;
each R 4 and R 5 is independently selected from hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; or R 4 and R 5 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
each R 6 , R 6a , R 6b , and R 6c is independently selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; aryl; or C 3-6 cycloalkyl;
each R 7 and R 8 is independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; or R 7 and R 8 are joined together with the atom or atoms to which they are attached to form a spirocyclic heterocyclyl, a spirocyclic carbocyclyl, a fused heterocycle, or a fused carbocyclyl;
each R 9 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy, or halogen; or two adjacent R 9 are joined together with the atoms to which they are attached to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;
each R 10 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; aryl; C 3-6 cycloalkyl; or cyano;
each R 11 is independently selected from hydrogen, alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; halogen; haloalkyl; or cyano;
each R 13 and R 14 is independently selected from hydrogen, alkyl, haloalkyl, aryl, or C 3-6 cycloalkyl;
R 15 is selected from hydrogen, alkyl, haloalkyl, (carbocyclyl)alkyl, aryl, or C 3-6 cycloalkyl
each R 16 and R 17 is independently selected from hydrogen, acyl, alkyl, haloalkyl, aryl, or C 3-6 cycloalkyl; or R 16 and R 17 are joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
each R 2a , R 3a , R 2b , R 3b , R 2c , and R 3c is independently selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or each of R 2a and R 3a , R 2b and R 3b , or R 2c and R 3c are independently joined together with the atom to which they are attached to form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
m is independently an integer from 1-3;
n is an integer from 0-3;
k is an integer from 0-3;
p is an integer from 1-2;
q is an integer from 1-6;
each s and u is independently an integer from 0 to 6; and
represents a single or double bond.
472 . (canceled)
473 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein
A is an acetylene or selected from the group consisting of
wherein each * is a point of attachment of A to L 1 or L 3 , and wherein the rings in A are optionally substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo;
B is an acetylene or selected from the group consisting of
wherein each * is a point of attachment of B to L 1 or L 3 , wherein the rings in B are optionally substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo;
G together with the atoms to which it is attached forms a ring system selected from 6-11 membered aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl, and 4-11 membered carbocyclyl, wherein the ring system is optionally with one or more substituents selected from alkyl, amino, haloalkyl, halogen, or oxo;
is selected from
or optionally substituted variants thereof;
each Y 2 is independently selected from —CH═ or N;
each Y 3 is independently selected from C(R 6 ) 2 , NR 6 , O or S;
each Y 5 is independently selected from NR 6 , O or S;
each C 3-7 cycloalkyl, C 3-7 heterocyclyl, and 5-10 membered heteroaryl of R 2 or R 3 is optionally substituted with one or more substituents selected from alkyl, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo; and
each R 12 is independently selected from hydrogen; alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and alkoxy; acyl; C-carboxy; C-amido; sulfinyl; sulfonyl; or S-sulfonamido.
474 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein the compound of Formula (XII) is also represented by Formula (XIIa):
wherein A is selected from acetylene,
wherein the rings in A are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo; and
B is selected from acetylene,
wherein the rings in B are unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, sulfonyl or oxo.
475 . (canceled)
476 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein D is —C(O)OR 1 .
477 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein both A and B are
each unsubstituted or substituted with one or more substituents selected from alkyl, amino, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, cyano, or oxo.
478 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein one of A or B is
and the other A or B is selected from
479 . The compound or pharmaceutically acceptable salt thereof of claim 478 , wherein A is
and B is selected from
480 . The compound or pharmaceutically acceptable salt thereof of claim 478 , wherein B is
and A is selected from
481 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein one of A or B is acetylene and the other A or B is selected from
482 . (canceled)
483 . (canceled)
484 . (canceled)
485 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein C is selected from
486 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein C is selected from
487 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein C is selected from
wherein R 10 is selected from hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl.
488 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein C is selected from
wherein R 10 is selected from hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl.
489 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein m is 1.
490 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 1 is hydrogen.
491 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein at least one of R 2 and R 3 is halogen or haloalkyl.
492 . (canceled)
493 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 2 is hydrogen and R 3 is selected from optionally substituted cyclobutyl.
494 . (canceled)
495 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 2 is hydrogen and R 3 is selected from optionally substituted oxetane.
496 . (canceled)
497 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 2 is hydrogen and R 3 is selected from optionally substituted thiazolyl or optionally substituted oxazolyl.
498 . (canceled)
499 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 2 and R 3 are joined together with the atom to which they are attached to form a C 3-6 cycloalkyl substituted by one or more halogen.
500 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein R 6 is hydrogen.
501 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein each of L 1 and L 2 is a single bond.
502 . (canceled)
503 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein L 5 is a single bond.
504 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein L 5 is a —O— linker.
505 . The compound or pharmaceutically acceptable salt thereof of claim 471 , wherein
506 . (canceled)
507 . (canceled)
508 . (canceled)
509 . The compound or pharmaceutically acceptable salt thereof of claim 471 , selected from compounds of Tables 12A and 12B, and pharmaceutically acceptable salt thereof.
510 . The compound or pharmaceutically acceptable salt thereof of claim 471 , selected from compounds IT123, IT136, IT150, IT151, IT172 and IT228 of Table 13.
511 .- 666 . (canceled)
667 . A pharmaceutical composition comprising an effective amount of a compound of claim 33 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
668 . A method for treating, preventing, reversing, halting, or slowing the progression of fibrosis, comprising administering an effective amount of a compound of claim 33 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.
669 . (canceled)
670 . The method of claim 668 , wherein the fibrosis is selected from pulmonary fibrosis, dermal fibrosis, kidney fibrosis, or liver fibrosis.
671 . The method of claim 670 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
672 . (canceled)
673 . The method of claim 668 , wherein said compound, the pharmaceutical acceptable salt thereof, or the pharmaceutical composition is administered by inhalation.
674 . (canceled)
675 . (canceled)
676 .- 730 . (canceled)
731 . A pharmaceutical composition comprising an effective amount of a compound of claim 441 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
732 . A method for treating, preventing, reversing, halting, or slowing the progression of fibrosis, comprising administering an effective amount of a compound of claim 441 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.
733 . The method of claim 732 , wherein the fibrosis is selected from pulmonary fibrosis, dermal fibrosis, kidney fibrosis, or liver fibrosis.
734 . The method of claim 733 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
735 . The method of claim 732 , wherein said compound, the pharmaceutical acceptable salt thereof, or the pharmaceutical composition is administered by inhalation.
736 . A pharmaceutical composition comprising an effective amount of a compound of claim 471 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
737 . A method for treating, preventing, reversing, halting, or slowing the progression of fibrosis, comprising administering an effective amount of a compound of claim 471 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.
738 . The method of claim 737 , wherein the fibrosis is selected from pulmonary fibrosis, dermal fibrosis, kidney fibrosis, or liver fibrosis.
739 . The method of claim 738 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
740 . The method of claim 737 , wherein said compound, the pharmaceutical acceptable salt thereof, or the pharmaceutical composition is administered by inhalation.Join the waitlist — get patent alerts
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